Pyridindoles and method of manufacture



Patented June 16, 1953 PYRIDINDOLE'S AND -METI1IQD; OE MANUFACTURERobert Duschinsky, Essex Fells, N'. J assignor-to Hofimann-La RocheInc., Nutley, N. J., a corporation of New Jersey No Drawing.Applieationlulyli,19,49; Serial No. 105,961;

11 ,Clai'mSL (01. 260-296 The present: invention, relates to;9.-R.-2.-R1- 1,2;3,4- -tetrahydro-- 91-1.- pyrid(3,4,-b) indoles,thesalts thereof; and-1 the process: for; producing; the

novel. compounds, Rbeing anaryljor, aralkylradical; such. as a phenyl orbenzyl radical, and R1- being: hydrogen: or a, lower alkyl. radical,such as methyl, ethyl; and the like. The new compounds have-usefulmedicinal properties, for xample, asspasmolytics and adrenolytics.

Chemically the compounds; in, the form-f their free: bases, can be;represented, by the; following formula:

wherein R; and'R1 have thesamemeaningalreadyassigned thereto.

In general, the new compounds (I) canbeprepared by reacting. withformaldehyde: a l-R:-3'.-

(fl-aminoethyDindole (II), of thefollowing. formula:

preferably-in theiorm of its salt, R and R1 hav-v ingthe same meaning asmentioned above;

The indoles (II) are new compounds. can be prepared by reacting al-R-l-phenyl-hydrazine with diethyl -aminobutyracetal, in the presenceof an acid condensing agent, such as hydrochloric acid. The reactionresults in the corresponding salt of the 1-R-3-(fi-R1NI-IC2HU- indoles(II) wherein R1 is hydrogen. In order to obtain the correspondingindoles where-R1 is a lower alkyl radical such as methyl, the indolewherein R1 is hydrogen is alkylated by known methods such as, forexample, by first reacting the indole with p-toluenesulfonyl chloride,then alkylating the resulting 1-R-3(B-tosylaminoethyDindole as, forexample, with methyl iodide, and subsequently removing the tosylradical, from the 1-R-3- (N methyl-p-tosylaminoethyl) indole. In thereaction with formaldehyde and the salts of the'I-R-3- (fi-R NI-ICHQ-iIIQOIES ('II), the- They 2- corresponding salts of the pyridindolecompound (I) are directly obtained. The salts of compounds (I) and-(II)carrbe-convertedto the rree bases by treatment with an alkalinecompound;

such asammon-ia; sodium hydroxide or sodium carbonate, and-the like; Toformthe quaternary ammonium salts, the free bases are treated withaquaternizingagent; suchas an alkyl halide-ion example, methyl iodide,ethyl iodide; methyl"- p-toluene sulfonate, dimethyl' sulfate,andthelika The-free base (I): whereRa ishydrogen, asrwell as the freebase (II) canbe acy-lated by treatment with: arr acid anhydride-onacidchloride; orby employing a carboxylicacidatelevated tern-- perature.Thus, the- 1present'invention also'eme braces the N-monoacylatedderivatives 0% com-- pounds (I) and (II).

The following examples will serve to illustrate the invention:

To a solution of 2;;4 grams of as-diphenylhydrazine hydrochloride in 10cc. of; water heated; to 5 060 0'. there were added 1.61 gramsofg'diethyl 'y-aminobutyracetal. The. mixture, was

heated; to C. and 6, cc, of concentrated (37- 38.5%) hydrochloric acid,were added whereupon the temperature rose to, C: Upon cooling1-pheny1-3- (fl-aminoethyl) indole hydrochloride crystallized. Thecompound was washed with water, then with Dry Ice-cooled ethanol and.finally with ether. After recrystallization irom. ethanol, the compoundmelted; at 237 239 C; The free base was readily obtained as an oil bytreatingthe hydrochloride with; sodium hydroxide solution,

Upon mixing the free base with acetic anhydride and permitting thereaction migrture tostand at 2030 C; for- 16 hours, the acetylderivative; 1-phenyl-3- (5-acetylaminoethyl-)indole was obtained. Afterwashing with a 5% sodium carbonatesolution and recrystallization fromaqueous ethanol, the compound melted at 1232-1-33- C]:

An ether solution of the base obtained from 1 gram of Y 1 -pheny1-3-B-aminoethyl) indole hydrochloride by treatment with a sodium hydroxidesolution was shaken with 2'- grams of methyl iodide-and 3 cc. of 5-- Nsodium hydroxide'solution. A crystalline mass of [2'-(1'-phenyl-3"-indolyD-ethyl]trimethylammoniumiodide formed 3 EXAMPLE 2Q-phenyZ-I,2,3,4-tetrahydro- 9H myrid (3,4 -l)) indole The compound,after washing with ethanol and ether, melted at 260-262 C.

The free base was obtained by treating 9.47 grams of the hydrochloridewith 6.5 cc.v of 5 N sodium hydroxide and 100 cc. of water. The oilwhich separated was extracted with ether, the ether extract was driedwith sodium sulfate and the ether was evaporated. The residue was anoily base which became crystalline upon standmg.

The quaternary p-toluenesulfonate salt was obtained in the followingmanner: A solution of 1.24 grams of 9-phenyl-l,2,3,4-tetrahydro-9Hpyrid-(3,4-b)indole in 10 cc. of ether was mixed with 0.93 gram ofmethyl p-toluenesulfonate. The solution became cloudy and an oilprecipitated. The supernatant liquid was evaporated and the residue wasboiled with 5 cc. of N sodium hydroxide. An oil precipitated whichbecame crystalline upon cooling and addition of ether. After washingwith water. and ether and after recrystallization from water,9-phenyl-1,2,3,4- tetrahydro 2,2 dimethyl 9H pyrid(3,4 b) indoliump-toluenesulfonate was obtained which melted at 198-199 C.

EXAMPLE 3 1 -phenyZ-3- (p-methylamz'noethyl) indole A mixture of 8.17grams of l-phenyl-3-(eaminoethyDindole hydrochloride, 6.3 grams ofptqluenesulfonyl chloride and cc. of dry pyridine wasrefiuxed for 1%hours. After evaporation of thefnajor part of the pyridine in vacuo, 40cc.

was washed with a small amount of water and steam distilled to removethe aniline. The nonvolatile oily residue was taken up with ether anddried over sodium hydroxide. After filtering the solution and adding a.small amount of ethanol, it was acidified with 15 cc. 1 N ethanolichydrochloric acid. The crystalline l-phenyl-3-(6- methylaminoethybindolehydrochloride which formed was filtered and washed with a mixture ofethanol and ether. After two recrystallizations from 20 cc. of ethanoland 10 cc. of ether, the compound melted at 158-160 C.

EXAMPLE. 4

9-phenyZ-2-methyl-1,2,3,4-tetrahydro- 9H -pyrid(3 ,4-5) indole Asolution of 0.86 gram of l-phenyl-3-(flmethylaminoethybindolehydrochloride in 10 cc. of water was heated at 70 C. and mixed with 0.6cc. of 38.5% formaldehyde. After standing for two minutes at 70 C. thesolution was cooled and evaporated at 35 C. in vacuo to a syrup whichWas dissolved in ethanol. The ethanol was evaporated, and the residuetaken up with ethanol and ether; Upon cooling, 9-phenyl-2-methyl-1,2,3,l-tetrahydro-9H-pyrid(BA-b) indole crystallized in the form of itshydrochloride. After recrystallization from ethanol-ether, the compoundmelted at 221-222 C.

Upon treating the hydrochloride with an excess of sodium hydroxidesolution, the free base was obtained as an oil.

EXAMPLE 5 1 -benzyZ-3- (p-aminoethyl) indole To a solution of 59 gramsof l-benzyl-l-phenylhydrazine hydrochloride in 250 cc. of water atcrystallized. The crystalline mass was washed with concentratedhydrochloric acid and ether.

' The crystals were then dissolved in 125 cc. of

The 1 phenyl 3 -(B tosylaminoethyl) indole thus obtained was dissolvedin 35 cc. of methanol and mixed with 5 cc. of 50% sodium hydroxidesolution and 5 cc. of methyl iodide. After standing'for 16 hours an oilprecipitated which was washed by dissolvingthe oil in methanol, chillingthe solution in Dry Ice and decanting the liquids After cooling, themixture was taken up with 40' The aqueous cc. of ether and 40 cc. ofwater. layer which formed was made strongly alkaline with 50% sodiumhydroxide and the resultant oil was extracted with ether. The etherextract evaporation of ether, the oil solidified.

ethanol and recrystallized by addition of 200 cc. of ether. The productmelted at 179-180 C. When 20 grams of the hydrochloride were dissolvedin 55 cc. of water warmed to 60 C. and '7 cc. of 14 N sodium hydroxidesolution were added, the base precipitated as an oil which was extractedwith and The ether. After drying the ether extract solid base melted at59-60 C.

1.08 grams of the free base were treated with 5 cc. of acetic anhydrideand the reaction 1nixture permitted to stand for 16 hours at 20-60 C.

Upon addition of 5% sodium carbonate solution and ether, 1-benzyl-3-(,B-acetylaminoethyl) indole crystallized. The compound, after washingwith 7 A mixture of 1.25 grams of l-benzyl-Zi-(flaminoethybindole, 0.62gram of nicotinic acid and 5 cc. of xylene was heated in an oil bath atC. for sixteen hours. Water formed during the reaction was distilled*offwith xylene, fresh xylene being added intermittently. Upon coolingthe reaction mixture, crystals separated and were purified bydissolution in boiling benzene and EXAMPLE 6 9-benzyZ-l,2,3,4-tetrahydro9H -'pyrid(3.4 b) indole A solution of 17.2 grams of l-benzyl-B-(B-aminoethyDindole hydrochloride in 300 cc. of water at 75 C. was mixedwith 12.5 00. of 38.5% formaldehyde. After standing at 75 C. for twominutes and cooling with ice, the 9-benzyl-1,2,3,4-tetrahydro-9l-I-pyrid(3,4-b)indole hydrochloride crystallized.After washing with water, ethanol and ether, the compound melted at 276C. The free base was precipitated from a boiling aqueous solution of thehydrochloride by addition of 6 cc. of N sodium hydroxide, and extractedfrom the cooled mixture with ether. The free base is a solid whichmelted at 80 C.

0.13 gram of the free base were treated with 0.14 gram ofp-toluenesulfonyl chloride and 1 cc. of one N sodium hydroxide. 1,2,3,4tetrahydro-9H-pyrid(3,4-b)indole separated in crystalline form. Itmelted at 170-171 C.

When a solution of 0.52 gram of 9-benzyl-1,2,3,4-9H-tetrahydropyrid(3,4-b) indole in 25 cc. of ether was mixedwith 0.37 gram of methyl p-toluenesulfonate, a crystalline mass wasobtained. This was filtered from the reaction medium and proved to bethe p-toluene sulfonic acid salt of9benzyl-1,2,3,4-9II-tetrahydro-pyrid(3,4- b)indole, M. P. 222-224 C.From the filtrate the quaternary ammonium salt, 9-benzyl-2,2-dimethyl1,2,3,4 tetrahydro-QH-pyrid(3,4-b) indolium p-toluenesulfonate, M. P.192-193 C.. was obtained as follows:

The filtrate Was evaporated to dryness and the residue was heated on asteam bath with 4 cc. of 0.5 N sodium hydroxide. After cooling, etherwas added and the initially oily material which formed becamecrystalline. It was filtered and washed with water and ether. The9-benzyl-2,2- dimethyl 1.2.3.4 tetrahydro-9H-pyrid(3,4-b)- indoliump-toluenesulfonate thus obtained was recrystallized from ethanol-ether.

EXAMPLE 7 1 -benzyZ-3- e-methylaminoethyl) indole A solution of 5 gramsof 1-benzyl-3-(B-aminoethyl) indole in 45 cc. of benzene was mixed witha solution of 3.88 grams of p-toluenesulfonyl chloride in cc. of benzeneand 13 cc. of 10% sodium hydroxide. After shaking the reaction mixturefor 10 minutes, the benzene mixture was separated and dried with sodiumsulfate. Addition of ethanol and petroleum ether resulted in theformation of crystals of 1-benzyl-3-(fitosylaminoethyDindole, melting atabout 90 C. Upon further recrystallization from ethanol-petroleui' nether, the compound melted at 91-92 C.

A mixture of 6.05 grams of l-benzyl-B-(ptosylamihoethyD-indole; 3 gramsof 50% sodium hydroxide, 3.06 grams of methyl iodide and '76 cc. ofethanol was shaken and then allowed to stand at 2030 C. for 16 hours.Upon cooling 1-benzyl- 3 -(Nmethyl-p-tosylaminoethyl)indolecrystallized. After washing with water and "aqueous ethanol, thecompound melted at 106-108'C. and after recrystallization from methanol,at 108-109 C. t

1.78 grams of 1-benzyl-3-(N-methyl-fi-tosylaminoethyDindole was mixedwith 1.72 cc. of aniline and 3.54 grams of aniline hydrochloride. Themixture was heated in an oil bath for 4 hours at about 200 C. in anatmosphere of carbon dioxide. After cooling the reaction mixture andadding 8 cc. of water and 30 cc. of ether, l-benzyl- 3 (BmethylaminoethyDindole hydrochloride crystallized. The product wasfiltered, and washed consecutively with ice water, ethanolether andfinally with ether. After recrystallization from ethanol, the compoundmelted at 213-214 C.

EXAMPLE 8 9-benzyl-2-methyl 1,2,3,4 tetrahydro-QH-pyrid(3,4-b) indole Asolution of 0.71 gram of 1-benzyl-3-(bmethylaminoethyl) indolehydrochloride in 10 cc. of water was heated at 70-80" C., and mixed with0.5 cc. of 38.5% formaldehyde solution. The mixture was allowed to standat 70-80 C. for 2 minutes. Upon cooling 9-benzyl 2 methyl-1,2,3,4-tetrahydro-91-I-pyrid(3,4-b) indole hydrochloride crystallized.The product melted at 225-226 C. The base was obtained as an oil when anaqueous solution of the hydrochloride was made alkaline with sodiumhydroxide.

I claim:

1. A compound of the group consisting of 9 R 2 R1 1,2,3,4 tetrahydro 9Hpyrid- (3,4-b)indole wherein R is a member of the group consisting ofmonocyclic aryl and monocyclicaralkyl radicals of the benzene series,and R1 is a member of the group consisting of hydrogen and lower alkylradicals, and lower alkyl quaternary salts and acid addition saltsthereof.

2. A method for preparing 9-R-2-R1-1,2,3,4

tetrahydro-9H-pyrid(3,4-b) indoles which come prises reacting a1-R-3-(fi-R1NI-ICzHr)indole salt with formaldehyde, R being a member ofthe group consisting o-f monocyclic aryl and mono.- cyclic aralkylradicals of the benzene series and R1 being a member of the groupconsisting of hydrogen and lower alkyl.

3. A method which comprises reacting 1- phenyl 303 aminoethyDindolehydrochloride with formaldehyde so as to obtain 9-phenyl-1,2,3,4-tetrahydro-9H-pyrid (3,4-b) indole hydrochloride.

4. A method which comprises reacting l-phenyl-3- (fl-methylaminoethyl)indole hydrochloride with formaldehyde so as to obtain 9-phenyl-2-methyl 1.23.4 tetrahydro 9H pyrid(3,4-b) indole hydrochloride.

5. A method which comprises reacting 1- benzyl 3 (,8 aminoethyhindolehydrochloride with formaldehyde so as to produce 9-benzyll,2,3,4tetrahydro 9H pyrid(3,4-b) indole hydrochloride.

6. A method which comprises reacting l-benzyl-3- (,s-methylaminoethyl)indole hydrochloride with formaldehyde so as to produce 9-benzyl-2-methyl 1,2,3,4'- tetrahydro 9H pyfld(3,4-b) methy1-9H-pyrid(3,4'b)indolium p-toluenesulindole' hydrochloride. V fonate.

'7. 9 phenyl 1,2,3,4 tetrah'ydro 9H pyrid- ROBERT DUSCHINSKY.(BA-bfindole hydrochloride.

8. 9 phenyl 2 --methyl 1,2 3,4 tetrahydro- 5 OTHER REFERENCES -P-Y A-hydrochlorida Hoshino, Chemical Abstracts, Vol. 29 (1935),

9. 9 benzyl 1,2,3,4 tetrahydro 9H pyridpage 2956 BA- d w ydr c Bericht-eder deut. Chem. Ges. 67B, pp. 2031 10. 9 benzyl 2 methyl 1,2,3,4tetrahydro- 2035 (1934) QH-WridEA-bJiHdOE hydrochloride- 10 Tatsui:Chemical Abstracts, vol. 22 (1928),

11. 9 phenyl 1,2,3,4 -.tetra,hydro 2;2 dipage 3415

1. A COMPOUND OF THE GROUP CONSISTING OF 9 - R-2-R1 - 1,2,3,4 -TERTRAHYDRO -9H - PYRID(3,4-B) INDOLE WHEREIN R IS A MEMBER OF THE GROUPCONSISTING OF MONOCYCLIC ARYL AND MONOCYCLIC ARALKYL RADICALS OF THEBENZENE SERIES, AND R1 IS A MEMBER OF THE GROUP CONSISTING OF HYDROGENAND LOWER ALKYL RADICALS, AND LOWER ALKYL QUATERNARY SALTS AND ACIDADDITION SALTS THEREOF.